Alkylphenoxy-alkylamines as gastric antisecretory agents

ABSTRACT

NOVEL ORTHO-SUBSTITUTED PHENOXYALKYLAMINES HAVING GASTRIC ANTISECRETORY ACTIVITY ARE PREPARED. A TYPICAL EMBODIMENT IS N,N-DIETHYL-2(2-CYCLOHEXYLTHYL)PHENOXY) ETHYLAMINE.

United States Patent "ice 3,709,892 ALKYLPHENOXY-ALKYLAMINES AS GASTRIC ANTISECRETORY AGENTS Peter R. Leeming, Peter E. Cross, and David A. Cox, Canterbury, and Joachim Augstein, Linford, England,

assignors to Pfizer Inc., New York, N .Y.

No Drawing. Filed June 8, 1970, Ser. No. 44,604 Claims priority, application Great Britain, June 12, 1969, 29,780/ 69 Int. Cl. 007d 29/18 US. Cl. 260293.83 17 Claims ABSTRACT OF THE DISCLOSURE Novel ortho-substituted phenoxyalkylamines having gastric antisecretory activity are prepared. A typical embodiment is N,N-diethyl-2[2-(2-cyclohexylethyl)phenoxy] ethylamine.

BACKGROUND OF THE INVENTION The invention relates to compounds having anti-histamine activity, and is particularly concerned with a novel class of ortho-substit uted phenoxyalkyl amines which have the property of blocking the actions of histamine at the so-called H receptor sites, e.g. those which influence gastric acid secretion, but have little or no ability to block the actions of histamine at the so-called H receptor sites, e. g., those which influence bronchial constriction.

SUMMARY OF THE INVENTION The novel compounds disclosed herein are selected from the group consisting of ortho-substituted phenoxyalkylamines of the formula:

and the pharmaceutically acceptable acid addition salts thereof, wherein R is alkyl of from 7 to 9 carbon atoms, cyclohexyl-methyl, cycloheXyl-ethyl, cyclohexyl-propyl or cycloheptyl-ethyl,

Y is aminoalkyl of the formula -AlkNR R in which R and R taken separately are each lower alkyl and R and R taken together with the nitrogen atom to which they are attached form a pyrrolidino, piperidine, morpholino, thiomorpholino, piperazino, azepino, or diazepino group and Alk represents a divalent alkyl group con taining from 2 to 4 carbon atoms; the free valences being located on different carbon atoms;

Or Y is an amino-cyclic group of the formula in which n is 0 to 3 and Z is a divalent group which completes a pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, azepine or diazepine ring, the nitrogen atom in said ring being separated from the oxygen atom to which the amino-cyclic group is attached, by a chain of from 2 to 4 carbon atoms;

And R is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkanoyl or a-oximino-lower alkyl.

In addition, there is disclosed a composition in dosage unit form useful for alleviating excess gastric acid secretion in a host comprising a pharmaceutical carrier and from about 12.5 mg. to about 500 mg, preferably from 3,709,892 Patented Jan. 9, 1973 about 50 mg. to about 200 mg. (expressed as the weight of the free base) of a compound having the formula:

and the pharmaceutically acceptable acid addition salts thereof, wherein R is alkyl of from 7 to 9 carbon atoms, cyclohexyl-methyl, cycloheXyl-ethyl, cyclohexyl-propyl or cycloheptyl-ethyl;

Y is aminoalkyl of the formula AlkNR R in which R and R taken separately are each lower alkyl and R and R taken together with the nitrogen atom to which they are attached form a pyrrolidino, piperidine, morpholino, thiomorpholino, piperazino, azepino, or diazepino group and Alk represents a divalent alkyl group containing from 2 to 4 carbon atoms, the free valences being located on different carbon atoms;

Dr Y is an amino-cyclic group of the formula in which n is 0 to 3 and Z is a divalent group which completes a pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, azepine, or diazepine ring, the nitrogen atom in said ring being separated from the oxygen atom to which the amino-cyclic group is attached, by a chain of from 2 to 4 carbon atoms;

And R is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkanoyl or a-OXlmil'lO-IOWGI' alkyl.

The term lower, applied to a snbstit utent group, means containing from 1 to 4 carbon atoms, and halogen means fluorine, chlorine, bromine or iodine.

DETAILED DESCRIPTION OF THE INVENTION In the general formula, R may be a straight or branched chain group, or may contain a cyclic group. For example, it may be a straight or branched chain heptyl, octyl or nonyl group, or a cyclohexyl-methyl, cyclohexyl-ethyl, cyclohexyl-propyl or cycloheptyl-ethyl group. Preferably, it is a primary hydrocarbyl radical, i.e., it is linked to the benzene ring by a methylene group. More preferably, it is an n-heptyl or 2-cyclohexyl-ethyl group.

When Y is a AlkNR R group, R and R may each be for example, a methyl, ethyl, propyl or butyl group or together with the nitrogen atom may form, for example, a pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino, azepino or diazepino group. When R and R form with the nitrogen atom a saturated heterocyclic group which contains a further nitrogen atom, then such further nitrogen preferably carries a lower alkyl or benzyl group as substituent.

When Y is a ---AlkNR R group, Alk-- may be, for example, an ethylene, propylene, ethyl-substituted eth ylene, dimethyl-substituted ethylene, trimethylene or tetramethylene group.

When Y is a group, C H may be, for example a methylene, ethylidene, ethylene, propylene or trimethylene group, and the heterocyclic ring completed by Z may be, for example, a pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, azepine or diazepine ring, provided that any nitrogen atom in the ring is separated by at least 2 carbon atoms from the oxygen atom to which the group is attached.

Thus,

may be, for example, a 3-pyrrolidinyl or 3- or 4-piperidinyl group, a 2- or B-pyrrolidinylmethyl or 2-, 3- or 4- piperidinylmethyl group, a 2-(2- or 3-pyrrolidinyl) ethyl or 2-(2- or 3-piperidinyl)ethyl group, or a 3-(2-pyrrolidinyl)-propyl or 3-(2-pipe1idinyl)propyl group. Any nitrogen atom in Z is preferably substituted with a lower alky or benzyl group while any carbon atom in PREPARATIVE METHODS (1) The compounds of the invention can be prepared from the appropriate ortho-substituted phenol, of the formula:

by (a) reaction with an alkali metal compound in an inert solvent to form the alkali metal phenate and then with the appropriate halide, of the formula:

where hal represents a halogen atom, to yield the required product direct;

(b) Reaction (under basic conditions) with a compound of the formula: hal-Alk-Q, where Q is halogen or other leaving group, e.g. an aryl sulfonyloxy group, such as benzene sulphonyloxy or p-toluene sulfonyloxy, to form a compound of the formula:

which is then reacted wtih the appropriate secondary amine H'NR R (c) Reaction wtih a halo-alkanol of the formula: hal-AlkOH, under similar conditions to (b) to form a compound of the formula:

which is converted to the halide, e.g., by reaction with thionyl chloride, and then reacted with the appropriate secondary amine as in (b); or (d) reaction with an alkali metal compound to form the phenate as in (a) and then with a lower alkyl ester of a halogeno-acid of the formula: hal-Alk-COR where R is a lower alkyl group, and Alk is a saturated aliphatic hydrocarbon group containing up to 3 carbon atoms, to yield a compound of the formula:

which is then converted to the appropriate amide (optionally via the free acid and acid chloride) by reaction with the amine HNR R and finally reduced with lithium aluminum hydride to yield the required product.

In the methods 1(a) and (d), the inert solvent may, for example, be toluene or dimethyl formamide. The formation of the phenate may be carried out by adding sodium hydride cautiously to the solution of the phenol and then heating. Reaction with the halide or halogenaacid ester (e.g., the chloride or chloroester) may be carried out at reflux temperature.

In methods 1(b) and 1(c), the reaction of the phenol with the compound hal--Alk-Q or with the halo-alkanol (e.g. bromo-alkanol) may be carried out under reflux in methanolic potassium hydroxide, ethanolic sodium ethoxide or acetone/potassium carbonate solution.

Subsequent reactions with the secondary amine may be carried out in any suitable inert solvent, e.g. ethanol, under reflux conditions. As a modification of these methods, a primary amine H NR may be used instead of the secondary amine HNR R and the product alkylated in conventional manner to yield a compound of the invention in which R and R are each a lower alkyl group.

(2) Compounds of the invention in which R is a primary hydrocarbyl radical, may also be prepared (a) When R is hydrogen, or a lower alkyl or allcoxy group, from a salicylaldehyde derivative of the formula:

R CHO by the Grignard reaction wtih magnesium and a halide of the formula halR where R -CH is equivalent to R to yield a compound of the formula:

which is then reduced, e.g., with hydrogen in the presence of a suitable catalyst; or (b) when R is hydrogen or a lower alkyl group, from a lower alkyl ether of salicylaldehyde itself, by similar reaction with the Grignard reagent and subsequent reduction, to yield a compound of the formula:

where R' is lower alkyl, the ether being converted to the free phenol by conventional methods and then reacted according to any of the preparations (1) (a), (b) or (c).

In the preparations (2) (a) and (b) the =Grignard reagent is prepared in the usual Way from magnesium and the appropriate halide in a suitable solvent, e.g. ether, and the appropriate aldehyde is then added slowly in the same solvent to the cooled solution of the Grignard reagent. The mixture is then heated to complete the reaction and the magnesium complex decomposed with acid at about 0. The subsequent reduction may be carried out with hydrogen in the presence of a palladiumon-carbon catalyst in an acid medium, e.g. at 50 and 50 p.s.i. in ethanolic hydrochloric acid, or in the presence of Raney nickel as catalyst.

(3) Compounds in which R is a primary hydrocarbyl radical and R is hydrogen, halogen, or a lower alkyl or alkoxy group may also be prepared from ortho-acyl phenols of the formula:

by (a) reduction with zinc and hydrochloric acid, with hydrazine in a suitable solvent, or with hydrogen in the presence of a suitable catalyst, followed by reaction according to any of the preparations (1) (a), (b) or (c); or (b) reaction first according to any of the preparations (1) (a), (b) or (c) to yield a compound of the formula:

followed by reduction as in (a). In each case, the reduction with hydrogen may be carried out as in preparation (2), and in the cases where R is halogen R may be simultaneously replaced by hydrogen.

The starting materials for preparation (3), i.e. acyl phenols of the aforementioned formula, can be readily prepared from the corresponding phenyl carboxylate by the Fries rearrangement reaction, with aluminum chloride or similar Lewis acid catalysts:

When R is hydrogen, however, the reaction gives a mixture of ortho and para isomers which have to be separated to give the required ortho-acyl phenol.

In each preparation, the final product may be obtained as free base by precipitation or by removal of solvent under reduced pressure, and purified by addition of water, extraction into a suitable solvent, drying, filtration and evaporation under reduced pressure. Acid addition salts may be obtained in the usual manner by addition of the appropriate acid in a suitable solvent to the liquid base, or to a solution thereof, and collection of the precipitate. Purification is carried out in the usual manner by recrystallization from a suitable solvent.

The compounds of the invention have been found to be potent Hf-antagonists, i.e. blockers of the action of histamine at H receptor sites. This has been shown in tests in which their inhibiting effect on histamine-induced gastric acid secretion has been measured in experimental animals. In one of such tests, anaesthetised rats are sensitised by intravenous injection of carbachol (carbamoyl choline chloride) and are then injected intravenously with a standard dose of histamine and the pH of the gastric contents is measured over a short period, until it stabilizes. The test compound is then administered, also intravenously and the pH of the gastric contents is measured over a further period, until the inhibiting effect of the compound is no longer apparent. A 50% inhibition of the effect of histamine on pH, at a dose of 10 mg./ kg. has been found for many of the compounds of the invention, while the most potent have a 100% inhibiting effect at 5 mg./kg. or a 50% inhibiting effect at 2.5 mg./kg. or even less. The more potent compounds are also effective over a period of 3 to 4 hours after injection. In a similar test with anaesthetised cats, histamine is continuously infused before and during administration of the test compound.

By virtue of their Hf-blocking activity, the compounds of invention are useful for reducing gastric hyperacidity and therefore in the treatment of gastric ulcers and other conditions caused or exacerbated by gastric hyperacidity. They are also useful for relieving other conditions due to the actions of histamine at H receptor sites.

On the basis of the results obtained, the preferred com pounds have been found to be those having the formula:

in which R is heptyl or 2-cyclohexyl-ethyl group, R is a hydrogen or fluorine atom or a methyl or methoxy group, and Y is a group of the formula -AlkNR R or (as hereinbefore defined) which contains (1) a single, tertiary nitrogen atom separated from the oxygen atom by a chain of two carbon atoms only, (2) a total of from 6 to 9 carbon atoms and (3) a methylene group attached to the oxygen atom.

Thus Y is preferably, for example: a group of the formula CH CH NR R in which R and R together contain from 4 to 7 carbon atoms; a group of the formula CH CH(CH )NR R where R and R together contain from 3 to 6 carbon atoms, or a 1-alkyl-2- piperidyl-methyl group in which the l-alkyl substituent contains up to 3 carbon atoms.

The compounds of the invention can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such excipients as starch and lactose, or in capsules either alone or in admixture with excipients or in the form of elixirs or suspensions containing flavoring or coloring agents. They may be injected parenterally, for example, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other solutes, for example, enough salts or glucose to make the solution isotonic.

The invention is illustrated by the following examples.

EXAMPLE 1 N,N-diethyl-2- [2- 2-cyclohexyl-ethyl) phenoxy] ethylamine A 50% dispersion of sodium hydride (1.2 g.) was added in portions to a stirred solution of 2-(2-cyclohexylethyl) phenol (5.0 g.) in dry dimethylformamide (75 m1.) and the mixture then heated to for /2 hour. Z-(diethylamino) ethyl chloride (3.3 g.) in dimethylformamide (25 ml.) was slowly added, the mixture was refluxed for a period of 3 hours, then cooled and water (10 ml.) added. After evaporation of most of the solvent under reduced pressure, water (100 ml.) was added to the residue and the mixture is extracted twice with ether. The organic extract was washed with water, dried over sodium sulfate and filtered. Evaporation of the solvent then afforded the product as a pale yellow oil. Addition of an ethereal solution of citric acid gave a white precipitate of 9.1 g. of the citrate salt of the product, which was recrystallized from isopropyl alcohol and had M.P. l31.

Analysis.-Found (percent): C, 62.7; H, 8.2; N, 2.95. Calcd. for C H NO-C H O (percent): C, 63.0; H, 8.3; N, 2.8.

EXAMPLES 2 TO 39 The compounds in the following examples were prepared as in Example 1, from the appropriate substituted phenol and chloride Cl-Y. The analytical figures required by the empirical formula of each compound are given in brackets. Salt formation was carried out in the usual Way, using the appropriate acid.

Elemental analyses (percent) Salt produced and IMF. R (empirical formula) C H Oxylate, 164-5 m nN 32E104).-

Citrate, 127-8 n nN0.GaHaO1) Citrate, 94-5 -dO--- -CH;CH:N(C2H5)2--------- H mHnNODaHam) Citrate, 978

Oxalate, 120-12D.6

( mHuN 0.0211204).

Citrate, Mi-6 win 11........... l-ethyl-hexyl 17- n-Heptyi- -CH CH;N(C;|HB) 2.........'... Cl

(on uCiNQCqH Oy).

Citrate, 131-2" Guam C1 Citrate, 145-6" (CgqHazNO CLCOHBOI) Citrate 95-96" (cnfinnuoasov.

Citrate 118118.5

(CH IIN O) so. 1 so. 2

Citrate, 97-98" (C HnNO'CQHBO'I) 8D 60., 3 5 2m 7D 76 1M. 2\5I -0. .0 6 m m m 0 No a I, u 0 m 0 EC ma 2 6H mm m m mm m C H H m N m m /N m H c. m H H o o n m u n .W m m .u n n m m x w Citrate, 112-113 (czl isNo-oz sow).

Citrate, 139-40 (CMHMNO- CeHs01) Elemental analyses (percent) Salt produced and M.P. Example R Y R (empirical tormula) C H N 32 ..do 01H; H Hydrochloride, 187-188 71. 9 9. 8 3. 4

t (CnHuNOlICI). 72. 2 (9. 9) (a. s) CH2(.43I

33 n-Nonyl -CH2CH2-N(C1H5)2 H Oxalate, 121122 65.6 9.0 3.6

(CNHSJNCLCQHZO). (66. 1) (9. 25) (3. 7)

34 2-cyclohexy1-ethyl Same as above CH:CO-- Citrate, 118-119 62.4 7.9 2.4

(CnHuNO .CaH Ov) (62. 55) (8. l) (2. 6)

35 do C1H H Hydrochloride 159-160 72.0 9.5 3.8 (OnHuNQEICl). 71. 7 9. 7 4.

36 do CH:OHzN(CzH)1 F Citrate, 129130 61. 0 8.1 2.4 (CguH32FNO.CuHs07). (60. 8) (7. 85) 2. 7

37 do OH; H Hydrochloride, 170 71. 3 9. 7 3. 9 (CIlHJSNO-HCD- 71. e5) (9. 7) (3. 9) CH:(

as o elohe t l-methy. CH CH N(C H5). H Citrate, mas-150 63.0 8.1 3.0

y p y 2 7- (C2o 9:NO.CeHsO1). (63.0) (8.3) (2.8)

39 C clohex l-meth 1 0 H5 H Cit e.137138 64.0 7.8 2.3 y y y o..H..N0.o.H.o1 63. 9) (8.1) (2.8)

EXAMPLE 4O EXAMPLES 41 TO 44 (A) 1-bromo-3-(Z-n-heptylphenoxy) propane Z-n-Heptylphenol (48 g.) was slowly added to a stirred solution of potassium hydroxide (14 g.) in methanol (100 ml.). 1,3-Dibromopropane (202 g.) was then added in one portion and the mixture is refluxed on the steam bath for two hours before cooling and filtering the precipitated potassium bromide. Evaporation of the solvent left a residual oil which was distilled under reduced pressure, the pure product being the fraction (36 g.) collected between 138 and 146 at 0.6 mm./Hg pressure.

(B) 4-[3-(2-n-heptylphenoxy) propyl]-l-methyl piperazine The product of (A) (5.0 g.) and N-methyl piperazine (6.4 g.) in ethanol (100 ml.) were refluxed for 6 hours. After cooling and removal of solvent under reduced pressure, water (100 ml.) was added and the mixture made just basic with 2 N sodium hydroxide followed by extraction twice with ether. The combined organic extracts were dried, filtered and evaporated to give a residual oil that was held for 1 hour at 60 C. and 1 mm. pressure in order to remove excess N-methyl piperazine.

The maleate salt was formed in the usual manner and recrystallized from ethanol, to yield 3.5 g. of the dimaleate, M.P. l9l-192 C.

Analysis.-Found (percent): C, 61.8; H, 7.7; N, 4.7. Calcd. for C H N O2C H O (percent): C, 61.7; H, 7.85; N, 5.0.

The compounds in the following examples were prepared as in Example 40 from the appropriate substituted phenol, 1,3-dibromopropane and the appropriate amine, salt formation being carried out in the usual way, using the appropriate acid. In the case of Examples 41 and 44, where the amine (diethylamine) is volatile, reaction was carried out in a sealed bomb at C. instead of under reflux conditions.

EXAMPLE 45 The product of Example 34 was added to a solution of hydroxylamine hydrochloride (1.0 g.) and sodium acetate (2.0 g.) in ethanol (50 ml.). The mixture is stirred, warmed on the steam bath for 1 /2 hours and cooled. The ethanol was then evaporated off under reduced pressure and water (50 ml.) added to the residue, which is extracted twice with ether (25 ml), evaporated and dried to give N,N-diethyl-2-[2-(2-cyclohexylethyl) 4 (l oximinoethyl)phenoxy] ethylamine, as a colorless oil.

Addition of ethereal citric acid gives the citrate salt, which is recrystallized from methanol/ethylacetate as a white solid (1.8 g.), M.P. Ill-113.

Analysis.Found (percent): C, 60.8; H, 7.8; N, 4.9. Calcd. for C H N O C H O (percent): C, 60.85; H, 8.0; N, 5.1.

EXAMPLE 46 (1) Sodium hydride (50% dispersion, 4.8 g.) was added portionwise to a solution of 2-(Z-cyclohexylethyl)phenol Elemental analysis (percent) Salt produced and M.P. Example R Y R (empirical formula) C H N 41 n-Heptyl CHzCH:CH2-N(C2H5)7 H Oxalate, 912 (CmH;5N0-O.Hz0.)- 66. 8 9. 1 3. 2

as. s) 9. 4) (a. s)

42 do Di-hydrochloride, 229-30 67. 4 9. 0 5. 3

' 2CH2 C r-'N /N CH2 CsHs (CflHmNgO -2HC1) (67. 3) (8. 8) (5. 8)

43 -.do H Oxalate, 109110 (CQOHlINO-CQ IOA) 66. 8 8. 7 3. 3

CHzCHz CHz-N (67. 1) (9. 0) (3. 6)

44 2-cyclohexylethyl CHzCH2CHr-N (C2115): H Citrate, -6 (O11Hl5N0-CQHB01) 63. 8 8. 1 2. 5

(20 g.) in dry dimethyl formamide (100 ml.) and the mixture heated to 80 for 1 hour. Chloroethylacetate (12.1 g.) is then added and the mixture refluxed tor 4 hours, cooled, poured into water, extracted with ether, evaporated and dried in the usual manner. High vacuum distillation gives 14.1 g. of ethyl 2-(2-cyclohexyl-ethyl)phenoxyacetate as a clear liquid.

(2) This ester (25 g.) is added to ethanolic sodium hydroxide (150 ml.) and warmed overnight on the steam bath. It is then evaporated to /s volume, added to water, extracted with ether, acidified with hydrochloric acid, extracted three times with chloroform (50 ml.) and evaporated to give 18.5 g. of crude 2-(2-cyclohexyl-ethyl) phenoxyacetic acid.

'(3) The acid is treated with thionyl chloride, and the acid chloride so formed (4.0 g.) was slowly added in benzene (30 ml.) to a solution of isobutyl piperazine (2.0 g.) in benzene (40 ml.). A rapid reaction takes place and a gelatinous precipitate was formed. The mixture was refluxed on a steam bath for 1 hour, cooled and then evaporated to near dryness under reduced pressure. Water 100 m1.) is then added to the residue, basified with NaOH and the mixture extracted with chloroform (50 ml.). Working up the chloroform extract in the usual manner atforded 4.6 g. of l-isobutyl-4-[2-(2-cyclohexylethyl)phenoxyacetyl] piperazine as a dark brown oil.

(4) This amide (4.6 g.) was slowly added to lithium aluminum hydride (1.1 g.) in dry ether (200 ml.) and the mixture stirred and refluxed for 6 /2 hours. N aqueous sodium hydroxic solution (1.8 ml.) was then added to decompose the excess LiAIHg and the mixture filtered. The filter cake is well washed with ether, the filtrates combined, dried and evaporated to give a mobile yellow oil. Addition of ethereal I-ICl gave 2.8 g. of 1-isobutyl-4-{2-(2-{2- cyclohexylethyl}phenoxy)ethyl]-piperazine di-hydrochloride which was recrystallized from isopropyl alcohol, MJP. 255-256.

Analysis.Found (percent): C, 64.45; H, 9.3; N, 6.1. Calcd. for C H N O.2HCl (percent): C, 64.7; H, 9.5; N, 6.3.

EXAMPLE 47 (1) Cyclohexylmethylmagnesium bromide (35.4 g.), 0.2 :mole was prepared in ether (610 ml.) in the usual manner from cyclohexylmethyl bromide and magnesium. Z-Diethylaminoethoxy benzaldehyde (44.2 g., 0.2 mole) in ether (60 ml.) was added slowly to the cooled Grignard reagent. At the completion of the addition the mixture was heated under reflux for 3 hours, and then decomposed with 5 N hydrochloric acid in the presence of ice. The free base art the product was liberated by the addition of ammonium chloride (42.8 g.) and dilute ammonia and the separated ethereal layer removed. The aqueous phase was extracted twice further with ether (150 ml. total) and the ether extracts pooled and washed with dilute ammonia. Ether was removed by evaporation on a water bath and the residual oil distilled in vacuo. The fraction of B.P. l80-186/0.3 mm. (29.8 g.) was collected and shown to consist of 95% pure N,N-diethyl-2-[2-(2-cyclohexyl-l-hydroxyethyl)phenoxy]ethylamine as free base.

(2) The product of 1) (20 g.) was dissolved in ethanol (100 ml); 36% 'w./v. hydrochloric acid (8 ml.) and 5% palladium on carbon catalyst (5 g., i.e. 2.5 g. of catalyst wetted with an equal weight of water) were added. The suspension was hydrogenated at 50 p.s.i.g. and 50 C. for 2 /2 hours, when hydrogen uptake ceased. Catalyst was filtered off and the filtrate was treated with an excess of 20% w./v. sodium carbonate solution (50 ml.). Most of the remaining ethanol was removed by distillation in vacuo and the residue extracted with ether (3 X 50 ml.). Evaporation of the ether yielded 16.4 g. of N,N-diethyl-2-[2- (2-cyclohexylethyl)phenoxy]ethylamine as an oil. This was dissolved in ether (150 ml.) and a solution of citric acid monohydrate in ethyl methyl ketone (11.4 g. in 75 ml.) added slowly to the stirred solution. A colorless voluminous precipitate separated which was filtered, washed with ether and dried in vacuo at 40 C. to yield 25.8 g. of the citrate, MZP. 128-130, identical with the product of Example 1.

Analysis.-Found (percent): C, 63.60; H, 8.50; N, 2.71. Calcd. for C H NO.C H 0-; (percent): C, 63.01; H, 8.34; N, 2.83.

EXAMPLE 48 (1) 2-Cyclohexylacetyl-4-chlorophenol (252.5 g., 1.0 mole) in dimethylformamide (600 ml.) was added over 1 hour to a suspension of sodium hydride oil dispersion (48 g., 1.0 mole) in dimethylformamide (400 m1.) at and the mixture obtained was stirred at 90-100 for a durther 1 /2 hours. Z-Dimethylaminoethylchloride (142 g., 1.05 mole) in dimethylformamide (200 ml.) was then added at 90 over 0.5 hour and the reactants heated at 90 for 3 hours. After cooling the reaction to 25 water (1 litre) was added cautiously, the solution obtained was extracted with chloroform (4X 750 ml.) the chloroform solution was backwashed with water (3X 500 ml.) and concentrated to an oil which was dissolved in dilute (5 N) hydrochloric acid (750 ml.) and backwashed with ether (3 X 250 ml.). The aqueous solution was adjusted to pH 9.5 with sodium hydroxide solution and extracted with chloroform (3X 250 ml.). The chloroform solution on concentration gave 345 g. of N,N-diethyl-2-(2-cyclohexylacetyl-4-chlorophenoxy) ethylamine as on oil. Purification of this product was achieved by formation of the citrate which was twice recrystallized trom isopropanol and had MP. 123-125".

(2) The product of (l) as citrate (11.2 g., 0.02 mole) dissolved in methylated spirit (100 mls.) was hydrogenated over 10% palladium on carbon (6 g.) at 60 p.s.i.g. and 80 until hydrogen uptake was complete (2 hours). The catalyst was filtered off and the solution concentrated to an oil which was suspended in water, adjusted to pH 9.5 with sodium hydroxide solution and extracted with chloroform (3 x 50 m1s.). The chloroform solution was dried over magnesium sulfate and concentrated to an oil to yield 5 g. of N,N-diethyl-2-[2-(2 cyclohexylethyl)- phenoxy1ethylamine as free base, B.P. 183-9 at 3.5 mm. Hg. This was converted by conventional means to the hydrochloride, M.P. 16l-2.

Analysis.Found (percent): C, 70.92; H, 10.12; N, 4.09; Cl, 10.75. Calcd. for C H NO.HCL (percent): C, 70.78; H, 10.10; N, 4.13; Cl, 10.45.

EXAMPLE 49 Formulation of tablets and capsules of N,N-diethyl-2- [2-(2-cyclohexylethyl)phenoxy]ethylamine hydrochloride described in Example 48 is efiected using the following ingredients:

1 Equivalent to 50 mg. of free base.

The ingredients are blended and compressed. The compressed pieces are then broken into granules and corn pressed into finished tablets.

Capsules Mg./ tablet N,N-diethyl 2 [2 (2 cyclohexyl-ethyl) phenoxy]ethylamine hydrochloride 1 56.0

Corn starch 127.0

Microcrystalline cellulose 127.0

Magnesium stearate 5.4

Sodium lauryl sulfate 0.6

Equivalent to 50 mg. of free base.

The ingredients are blended and filled into hard gelatin capsules of suitable size.

13 What is claimed is: 1. A compound selected from the group consisting of those of the formula:

and the pharmaceutically acceptable acid addition salts thereof wherein R is alkyl of from 7 to 9 carbon atoms, cyclohexyl-methyl, cyclohexyl-ethyl, cyclohexyl-propyl or cycloheptyl-ethyl; Y is aminoalkyl of the formula in which R and R taken separately are each lower alkyl and R and R taken together with the nitrogen atom to which they are attached form a pyrrolidino or piperidino group and Alk is a divalent alkyl group containing from 2 to 4 carbon atoms, the free valences being located on different carbon atoms; or Y is an amino-cyclic group of the formula in which n is to 3 and Z is a divalent group which completes a pyrrolidine or piperidine ring, the nitrogen atom in said ring being separated from the oxygen atom to which the aminocyclic group is attached, by a chain of from 2 to 4 carbon atoms; and R is hydrogen, halogen, lower alkyl, lower alkoxy or lower alkanoyl.

2. A compound as claimed in claim 1, in which R is n-heptyl or 2-cyclohexyl-ethyl; R is hydrogen, fluorine, methyl or methoxy; and Y contains a single, tertiary nitrogen atom separated from the oxygen atom by a two carbon chain, a total of from 6 to 9 carbon atoms and a methylene group attached to said oxygen atom.

3. A compound as claimed in claim 2, in which Y is CH -CH NR R where R and R together contain from 4 to 7 carbon atoms.

4. A compound as claimed in claim 3, in which R is 2-cyclohexylethyl, R and R are each ethyl, and R is hydrogen.

5. A compound as claimed in claim 3, in which R is 2-cyclohexylethyl, R and R are each n-propyl and R is hydrogen.

6. A compound as claimed in claim 3, in which R is n-heptyl, R and R are each ethyl and R is hydrogen.

7. A compound as claimed in claim 3, in which R is n-heptyl, R and R are each ethyl and R is methyl.

8. A compound as claimed in claim 3, in which R is 2-cyclohexyl-ethyl, R and R together with the nitrogen atom to which they are attached is piperidino and R is hydrogen.

9. A compound as claimed in claim 3, in which R is 2 cyclohexyl-ethyl, R and R together with the nitrogen atom to which they are attached is pyrrolidino, and R is hydrogen.

10. A compound as claimed in claim 3, in which R is 2-cyclohexyl-ethyl, R and R together wth the nitrogen atom to which they are attached is 2,6-dimethyl-piperidino and R is hydrogen.

11. A compound as claimed in claim 3, in which R is 2-cyclohexyl-ethyl, R and R are each ethyl, and R is methoxy.

12. A compound as claimed in claim 3, in which R is 2-cyclohexyl-ethyl, R and R are each ethyl and R is fluoro.

13. A compound as claimed in claim 2, in which Y is CH -CH(CH )-NR R wherein R and R together contain from 3 to 6 carbon atoms.

14. A compound as claimed in claim 13, in which R is 2-cyclohexyl-ethyl, R and R are each ethyl and R is hydrogen.

15. A compound as claimed in claim 2 in which Y is 1alkyl-2-piperidylmethyl and the l-alkyl substituent contains up to 3 carbon atoms.

16. A compound as claimed in claim 15, in which R is 2-cyclohexyl-ethyl, Y is lmethyl-2-piperidyl-methyl and R is hydrogen.

17. A compound as claimed in claim 15, in which R is 2-cyclohexyl-ethyl, Y is 1ethyl-2-piperidyl-rnethyl and R is hydrogen.

References Cited UNITED STATES PATENTS 2,337,572 12/ 1943 Rosenthal 260570.7

2,679,501 5/1954 Wenner 260247.7 C

3,091,616 5/1963 Petrow et al 260293.83

3,205,136 9/1965 Tedeschi 260570.7

3,255,196 6/1966 Debarre et al 260-29383 FOREIGN PATENTS 965,813 7/1949 Germany 260-247.7 C

OTHER REFERENCES Arch. Int. Pharm. 134: 106-112, 114, 116, 117, 122, 123, 124, 126-130 (1961), Abood et al.

JOHN D. RANDOLPH, Primary Examiner S. D. WINTERS, Assistant Examiner U.S. Cl. X.R.

424-244, 246, 248, 250, 267, 274, 327, 330; 260-239 B, 243 B, 247.7 C, 268 R, 293.8, 326.5 M, 326.5 J, 570.7 

